One of the most widely used biocompatible polymers for medical use is hyaluronic acid (HA). It is a naturally occurring polysaccharide belonging to the group of glycosaminoglycans (GAGs). HA and the other GAGs are negatively charged heteropolysaccharide chains which have a capacity to absorb large amounts of water. HA and products derived from HA are widely used in the biomedical and cosmetic fields, for instance during viscosurgery and as a dermal filler.
Water-absorbing gels, or hydrogels, are widely used in the biomedical field. They are generally prepared by chemical cross-linking of polymers to infinite networks. While native HA and certain cross-linked HA products absorb water until they are completely dissolved, cross-linked HA gels typically absorb a certain amount of water until they are saturated, i.e. they have a finite liquid retention capacity, or swelling degree.
Since HA is present with identical chemical structure except for its molecular mass in most living organisms, it gives a minimum of reactions and allows for advanced medical uses. Cross-linking and/or other modifications of the HA molecule is necessary to improve its resistance to degradation or duration in vivo. Furthermore, such modifications affect the liquid retention capacity of the HA molecule. As a consequence thereof, HA has been the subject of many modification attempts.
When preparing gels from biocompatible polymers, it is advantageous to ensure a low degree of cross-linking so as to maintain a high bio-compatibility. However, often a more dense gel is required to have a proper biomedical effect, and in such a case the biocompatibility will often be lost.
Some known soft-tissue augmentation treatments involving implants occasionally suffer from the drawback that the implant, or part thereof, migrates away from the desired site of treatment.
WO 87/07898 discloses a method for preparing HA films. Any gel formation shall be avoided until the cross-linking step, which involves drying of an aqueous solution of epoxy-activated HA into a film. It is inherent in the method that all other components in the cross-linking step must be volatile.
WO 2004/092223 discloses a method of producing a cross-linked HA gel by drying a mixture of HA and epoxide cross-linking agent without substantially removing the epoxide.
Similarly, WO 2011/109129 and WO 2011/109130 discloses a process of producing HA threads by drying HA in the presence of a cross-linking agent under non-denaturing conditions.
U.S. Pat. No. 5,827,937 discloses a process for preparing polysaccharides having a high degree of cross-linking.
WO 00/046253 discloses a method involving two types of cross-linking steps, each in the presence of a cross-linking agent, for increasing the degree of cross-linking of HA.
US 2007/0066816 discloses a process for preparing double-cross-linked HA, involving cross-linking of a HA substrate in two steps with an epoxide and a carbodiimide, respectively.
U.S. Pat. No. 6,852,255 discloses a method involving cross-linking a water solution of HA followed by shaping of the cross-linked HA, e.g. by the addition of an organic solvent to precipitate the cross-linked HA.
U.S. Pat. No. 4,716,224 relates to a method for producing cross-linked HA having increased resistance to enzymatic decomposition. It is mentioned that HA may be precipitated prior to addition of the cross-linking agent.
KR 2007/0004159 discloses a method of preparing cross-linked HA by subjecting HA in solid phase to a cross-linking agent in an organic solvent.
EP 2 199 308 relates to a method of producing cross-linked HA by disperging HA powder in aqueous alcohol prior to addition of a cross-linking agent.
U.S. Pat. No. 6,921,819 discloses a method for cross-linking HA in which a polyfunctional cross-linking agent is reacted with HA in the solid state during hydration thereof.
Despite these advances in the field, there remains a need for alternative methods of manufacturing cross-linked HA products having suitable liquid retention capacity and degradation profile, but with retained biocompatibility. In particular, it is desirable to minimize the degree of modification that is needed to obtain a HA gel product having a desired gel strength, which for instance can be measured as liquid retention capacity.